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1
Kohn, Meifania Monica. "Lipoprotein ontology: a formal representation of Lipoproteins." Thesis, Curtin University, 2013. http://hdl.handle.net/20.500.11937/1827.
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Lipoproteins serve as a mode of transport for the uptake, storage and metabolism of lipids. Dysregulation in lipoprotein metabolism, known as dyslipidaemia, is strongly correlated to various diseases such as cardiovascular disease. Lipoprotein Ontology provides a formal representation of lipoprotein concepts and relationships that can be used to support the intelligent retrieval of information, faciliate collaboration between research groups, and provide the basis for the development of tools for the diagnosis and treatment of dyslipidaemia.
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Soran, Handrean. "Glycation of Lipoproteins and the Role High Density Lipoprotein and Paraoxonase -1." Thesis, University of Manchester, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.532197.
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Espinosa, Garcia Irma Leticia. "Differential density lipoprotein profiling for the characterization of Lipoprotein(a)." Texas A&M University, 2006. http://hdl.handle.net/1969.1/4359.
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Lipoprotein(a) (Lp(a)) has been described as an emerging risk factor for cardiovascular
disease. The complexity of the Lp(a) molecule sets a challenge for the determination
of the risk it represents for the cardiovascular system. The objective of the
present study was to develop a rapid method for the separation, purification, density
measurement, and characterization of Lp(a) from serum using a procedure that is
isoform independent.
The objective was met by linking ultracentrifugation with affinity separations for
the specific separation of Lp(a) from other lipoproteins. The mean density distribution
of Lp(a) was determined by a differential density lipoprotein profile (DDLP).
For DDLP, the lipoprotein density distribution of a serum sample with elevated Lp(a)
levels was determined by ultracentrifugation using NaBiEDTA complex as a density
gradient. Lp(a) was removed from a second aliquot of the same serum sample by
carbohydrate affinity using wheat germ agglutinin (WGA). WGA was demonstrated
to have high specificity for Lp(a) in serum. The Lp(a)-depleted sample was ultracentrifuged
to obtain a lipoprotein density distribution in the absence of Lp(a). A
DDLP was obtained after subtracting the Lp(a)-depleted lipoprotein density profile
from the untreated lipoprotein density profile. DDLP gives relevant information of
the lipoproteins in serum such as density, Lp(a) isoform, and subclass characteristics.
Lp(a) was quantitatively removed from serum with a recovery efficiency of more than 80%. Lp(a) was purified by ultracentrifugation. Lp(a) obtained in this way
retained its inherent density and immunoreactivity. Lp(a) was further characterized
by gel electrophoresis and Western blot as well as by capillary electrophoresis.
Capillary electrophoresis demonstrated to be a powerful analytical technique for the
characterization of Lp(a) and apoprotein(a) isoforms.
The major outcome of this research was the effectiveness of using affinity separations
coupled with density ultracentrifugation for the isolation of pure Lp(a) from
serum and its isoform characterization based on density and electromobility. The
methodology developed and described here are relevant in a clinical setting for the
analysis of Lp(a).
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Hacquebard, Mirjam Rebecca. "Alpha-tocopherol acquisition by plasma lipoproteins and changes in lipoprotein profile after cardiac surgery." Doctoral thesis, Universite Libre de Bruxelles, 2008. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/216586.
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Alpha-tocopherol, the most abundant form of vitamin E in man, is transported in the circulation by plasma lipoproteins. It plays important roles, not only in preventing lipid peroxidation, but also in modulating several cell functions such as cell signaling and gene expression. While chylomicrons transport dietary alpha-tocopherol after intestinal absorption, LDL and HDL are the major carriers of alpha-tocopherol in fasting plasma and largely contribute to its delivery to cells and tissues. Exchanges of alpha-tocopherol occur between plasma lipoproteins. In addition, alpha-tocopherol transfers have also been observed, in both directions, between plasma lipoproteins and artificial chylomicrons such as intravenous lipid emulsion particles used in parenteral nutrition. In acute conditions, intravenous supply of vitamin E via lipid emulsions, which bypasses the intestinal tract, may offer some advantages over oral administration to rapidly increase alpha-tocopherol plasma concentration. However, many questions remain unanswered regarding kinetics and factors facilitating vitamin E exchanges between lipid emulsions and plasma lipoproteins. The first part of this work aimed at characterizing alpha-tocopherol transfers between alpha-tocopherol rich emulsion particles and plasma lipoproteins as well as the potential for plasma proteins to modulate such transfers. An in vitro model of incubation was used in which emulsion triglyceride concentration was relatively low and lipoprotein levels comparable to those commonly found in the circulation. Results indicate a high capacity for LDL and HDL to acquire extra-amounts of alpha-tocopherol by rapid mass transfers from alpha-tocopherol-rich emulsion particles. Data further shows that, at a fixed alpha-tocopherol concentration provided by emulsion particles, the limiting factor for alpha-tocopherol enrichment is not the capacity of plasma lipoproteins to accommodate extra-amounts of alpha-tocopherol but the facilitating effect of plasma proteins on alpha-tocopherol transfer, the duration of the incubation and possibly the competition between different acceptor particles. Two lipid transfer proteins, PLTP and CETP, appear to largely mediate facilitation of alpha-tocopherol transfer; however, other plasma proteins may be involved. Data further shows that alpha-tocopherol enriched LDL and HDL can readily transfer newly acquired alpha-tocopherol to cells, without any regulation by plasma proteins.Short-term prophylactic vitamin E supplementation has been suggested to be beneficial in some patients in acute conditions who present reduced plasma vitamin E concentrations in association with important changes in plasma lipids and severe oxidative stress. However, it was not clear whether low plasma vitamin E concentration in critically ill patients is related to changes in the composition of plasma lipoproteins or to a decrease in the number of alpha-tocopherol carriers. In the second part of this work, two clinical studies were conducted to analyze changes of lipoprotein concentration and composition in relation to inflammatory reaction and oxidative stress in selected subgroups of critically ill patients, namely patients undergoing cardiac surgery with different procedures. Important changes in LDL and HDL lipid content were observed, some of which contrast with previous observations made in critically ill septic patients. The reduced plasma level of alpha-tocopherol measured after cardiac surgery is entirely due to a reduced number of circulating LDL and HDL particles. Data suggests that such reduced number in alpha-tocopherol carriers post-surgery may impede the delivery of alpha-tocopherol to cells in conditions of increased requirements due to oxidative stress. Avoidance of extracorporeal circulation during cardiac surgery does not reduce inflammation-related changes in plasma lipids but largely prevents oxidative stress. This data on changes occurring in plasma lipoproteins may help to better define strategies against pro-inflammatory changes or oxidative stress. If further studies would confirm a clinical benefit with evidence-based rationale, alpha-tocopherol enriched lipid emulsions may be used to guarantee a sufficient alpha-tocopherol supply in acute conditions associated with fewer alpha-tocopherol transporters and increased requirements due to high risk of oxidative tissue injury.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Ma, Feng. "Clinical Assessment of Anti-Atherogenic Function of HighDensity Lipoprotein (HDL)." Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS583.
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Il a été bien établi chez l’Homme qu'il existe une forte association entre les faibles concentrations plasmatiques de cholestérol associé aux lipoprotéines de haute densité (HDL-C) et le risque accru de maladie cardiovasculaire (MCV). Augmenter le taux de HDL-C a donc été proposé comme stratégie thérapeutique visant à réduire le risque de MCV. En effet, les HDL présentent de multiples fonctions athéroprotectrices, notamment la capacité d’efflux du cholestérol, ainsi que des activités antioxydantes, anti-inflammatoires, vasodilatatrices, cytoprotectrices, anti-infectieuses et anti- thrombotiques. Cependant, des essais cliniques à grande échelle ont révélé que l'augmentation du HDL-C induite par un médicament ne réduisait pas nécessairement le risque CV. En outre, des études de randomisation mendélienne ont montré que des concentrations faibles de HDL-C déterminées génétiquement ne se traduisaient pas toujours par un risque accru de MCV. Récemment, plusieurs études épidémiologiques à grande échelle ont mis en évidence une dépendance en forme de U entre la maladie cardiovasculaire et les taux de HDL-C, établissant un lien entre un taux de HDL-C extrêmement élevé et un risque CV élevé. Afin de surmonter les limites du HDL-C en tant que facteur de risque CV, le concept de fonctionnalité des lipoprotéines HDL a été étudié, ce qui a permis de développer un test permettant la mesure de la capacité des HDL à faire de l’efflux de cholestérol comme approche de prédiction du risque. Cependant, ce concept révèle plusieurs faiblesses, telles que la préservation de l'efflux de cholestérol tissulaire chez les patients ayant un taux de HDL-C bas d'origine génétique. Dans la circulation, le métabolisme des HDL est intimement lié à celui des triglycérides (TG) par divers facteurs, notamment des enzymes, telles que la lipoprotéine lipase (LPL), et des protéines de transfert lipidique, telles que la protéine de transfert d'esters de cholestérol (CETP). La contribution des niveaux circulants de TG au risque élevé de MCV a été établie dans des modèles multivariés. On pense que les lipoprotéines riches en triglycérides (TGRL) contribuent à l'athérosclérose via leurs particules résiduelles produites lors de la lipolyse des TGRL par la LPL. Des études antérieures ont montré que les HDL sont capables d'empêcher l'accumulation de ces particules residuelles de TGRL dans la paroi artérielle. Il a donc été proposé que le faible taux de HDL-C représente un biomarqueur de niveaux élevés de résidus de TGRL générés par la lipolyse. On ignore actuellement si cette association peut expliquer la relation en forme de U entre le risque CV et le taux de HDL-C. En outre, les mécanismes sous-jacents à l'association entre le HDL-C, les résidus de TG et les MCV restent obscurs. Dans la présente étude, nous proposons une hypothèse selon laquelle les HDL circulants peuvent se charger en lipides, tels que le cholestérol libre (FC) et le phospholipide (PL), et des protéines provenants de la surface des résidus des TGRL générés au cours de la lipolyse médiée par la LPL, puis les transporter vers le foie dans un processus appelé le transport inverse des résidus (RRT). Nous suggérons en outre que les modifications de la RRT sous-tendent les relations entre HDL-C et MCV. Pour évaluer cette hypothèse, nous avons conçu un nouveau test in vitro évaluant les transferts lipidiques des TGRL aux HDL au cours de la lipolyse et l'avons appliqué à plusieurs populations de sujets présentant des taux plasmatiques de HDL-C différents. Les mécanismes de transfert de lipides de surface vers les HDL ont également été étudiés. Nous avons observé que les HDL, isolés par ultracentrifugation ou par déplétion plasmatique de l'apolipoprotéine B, acquéraient des lipides de surface, y compris FC et PL, des TGRL lors d'une lipolyse induite par le LPL à 37 ° C, en fonction du temps, comme l'a révélé la photométrie [...]It has been well established that there is a strong association between low concentrations of high-density lipoprotein-cholesterol (HDL-C) in human plasma and the risk of cardiovascular disease (CVD). Raising HDL-C level was therefore proposed as a therapeutic strategy to decrease CV risk. Indeed, HDL displays multiple atheroprotective functions, including cholesterol efflux capacity as well as antioxidative, anti-inflammatory, vasodilatory, cytoprotective, anti-infectious and anti-thrombotic activities. However, large-scale clinical trials revealed that drug-induced HDL-C raising did not necessarily reduce CV risk. Furthermore, Mendelian randomization studies reported that genetically determined low HDL-C concentrations did not always translate to increased risk of CVD. Recently, a U-shape dependence between CV disease and HDL-C levels was observed in several large-scale epidemiological studies, linking extremely high HDL-C to elevated CV risk. To overcome the limitations of HDL-C as a CV risk factor, a concept of HDL functionality was developed which resulted in the development of the measurement of cholesterol efflux capacity of HDL as a risk-predicting approach. However, this concept reveals several weaknesses, such as, preservation of tissue cholesterol efflux in patients with genetically low HDL-C. In the circulation, HDL metabolism is intimately linked to that of triglyceride (TG) by various factors, including enzymes, such as lipoprotein lipase (LPL), and lipid transfer proteins, such as cholesteryl ester transfer protein (CETP). The contribution of circulating TG levels to the elevated risk of CVD was established in multivariate models. Triglyceride-rich lipoproteins (TGRLs) are thought to contribute to atherosclerosis via their remnant particles produced during lipolysis of TGRLs by LPL. Earlier studies showed that HDL is capable of preventing TGRL remnants from accumulation in the arterial wall. Low HDL-C was therefore proposed to represent a biomarker of elevated levels of TGRL remnants generated by the lipolysis. It is presently unknown whether this association can account for the U-shape relationship between CV risk and HDL-C. In addition, mechanisms underlying the association between HDL-C, TG remnants and CVD remain obscure. In the present study, we propose a hypothesis that in the circulation HDL can acquire lipids, such as free cholesterol (FC) and phospholipid (PL), and proteins from TGRL surface remnants generated during LPL-mediated lipolysis, and subsequently transport them to the liver in a process termed reverse remnant transport (RRT). We further suggest that RRT alterations underlie the relationships between HDL-C and CVD. To assess this hypothesis, we designed a novel in vitro assay evaluating lipid transfers from TGRL to HDL during lipolysis and applied it to several populations of subjects greatly differing in plasma HDL-C levels; mechanisms of surface lipid transfer to HDL were also studied. We observed that HDL, isolated by ultracentrifugation or by apolipoprotein B depletion of plasma, acquired surface lipids, including FC and PL, from TGRL upon LPL-induced lipolysis at 37°C in a time-dependent fashion as revealed by photometry [...]
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Ooi, Esther M. M. "Regulation of lipoprotein transport in the metabolic syndrome : impact of statin therapy." University of Western Australia. School of Medicine and Pharmacology, 2007. http://theses.library.uwa.edu.au/adt-WU2007.0125.
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[Truncated abstract] The metabolic syndrome is characterized by cardiovascular risk factors including dyslipidemia, insulin resistance, visceral obesity, hypertension and diabetes. The dyslipidemia of the metabolic syndrome includes elevated plasma triglyceride and apolipoprotein (apo) B levels, accumulation of small, dense low-density lipoprotein (LDL) particles and low high-density lipoprotein (HDL) cholesterol concentration. However, the precise mechanisms for this dyslipoproteinemia, specifically low plasma HDL cholesterol, are not well understood. This thesis therefore, focuses on HDL, its structure, function and metabolism. However, lipoprotein metabolism is a complex interconnected system, which includes forward and reverse cholesterol transport pathways. Hence, this thesis also examines and discusses the metabolism of apoB-containing lipoproteins. This thesis tests the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that lipid regulating therapies can improve these kinetic abnormalities. The aims were first, to compare and establish the clinical, metabolic and kinetic differences between metabolic syndrome and lean subjects; and second, to determine the regulatory effects of statin therapy, specifically, rosuvastatin on lipoprotein transport in the metabolic syndrome. Five observation statements were derived from the general hypothesis and examined in the studies described below. The findings are presented separately as a series of original publications. Study 1 Twelve men with the metabolic syndrome and ten lean men were studied in a case-control setting. ... These findings explain the HDL raising effects of rosuvastatin in the metabolic syndrome. Collectively, these studies suggest that the dyslipidemia of the metabolic syndrome results from increased production rates of VLDL and LDL particles, reduced fractional catabolic rates of these lipoproteins, together with accelerated catabolism of HDL particles. Treatment with rosuvastatin increases the catabolic rates of all apoB-containing lipoproteins and at a higher dose, decreases LDL apoB production. These effects are consistent with inhibition of cholesterol synthesis leading to an upregulation of LDL receptors. Rosuvastatin decreases the fractional catabolism of HDL particles. The effects of rosuvastatin on HDL kinetics may be related to a reduction in triglyceride concentration and cholesterol ester transfer protein activity. These findings are consistent with the general hypothesis that apolipoprotein kinetics are altered in the metabolic syndrome, and that statin therapy improves these kinetic abnormalities.
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Gordon, Scott M. "The role of high density lipoprotein compositional and functional heterogeneity in metabolic disease." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1353100684.
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Toledo, Júnior Alceu de Oliveira. "MARCADORES BIOQUÍMICOS NAS DISLIPIDEMIAS E NO RISCO CARDIOVASCULAR: ANÁLISE COMPARATIVA À FÓRMULA DE MARTIN." Universidade Estadual de Ponta Grossa, 2018. http://tede2.uepg.br/jspui/handle/prefix/2712.
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Este estudo tem como objetivo avaliar comparativamente perfis de marcadores bioquímicos que melhor caracterizem e/ou associem-se às dislipidemias, na modalidade diagnóstica por ampliar a estratificação do risco cardiovascular ou no seu monitoramento para melhor condução. Para isso avaliamos o perfil lipídico composto por colesterol total, triglicérides, colesterol da lipoproteína de alta densidade e da lipoproteína de baixa densidade; esta com a fórmula de Martin, e ainda o colesterol em conteúdo que não faz parte das lipoproteínas de alta densidade, correlacionando-os com os marcadores: lipoproteína a, apoproteína B e colesterol da lipoproteína de baixa densidade; com uso do método homogêneo. Foram selecionados 1012 pacientes, segmentados por faixas etárias, sexo e condição de uso ou não de inibidores de produção hepática do colesterol. Para ampliar o poder dessa análise agrupada os exames realizados foram separados em subgrupos, considerando-se valores obtidos e metodologias utilizadas; correlacionando-se os resultados. A pesquisa foi realizada com variáveis qualitativas e quantitativas, procedendo-se ao uso de testes estatísticos não paramétricos para sua compreensão, distribuição e análise agrupada. Nossos resultados mostraram evidências que o risco cardiovascular não se associa apenas ao colesterol da lipoproteína de baixa densidade obtido pela fórmula de Martin, mas a outras variáveis, sob associação às seguintes análises comparativas: que o uso da apoproteína B amplia o diagnóstico de inclusão das dislipidemias em 43% usando valores referenciais sexo-independentes e com uma nova faixa de monitoramento em 84 mg/dL. Que o colesterol da lipoproteína de baixa densidade obtido pelo método homogêneo apresenta discordância analítica em +3,5% e tendo estratificação diagnóstica 48% superior. E que a lipoproteína a apresenta-se superior a 30 mg/dL em 26% dos pacientes, porém com prevalência e segmentação específicas nas mulheres entre 51 a 60 anos, sendo necessária sua análise numa aparente discordância, superior a 10 mg/dL, quando da comparação de resultados entre a fórmula de Martin e o método homogêneo.
This study aims to comparatively evaluate the profiles of biochemical markers that best characterize and / or associate with dyslipidemias, in the diagnostic modality by increasing the stratification of cardiovascular risk or its monitoring for better conduction. For this, we evaluated the lipid profile composed of total cholesterol, triglycerides, high density lipoprotein cholesterol and low density lipoprotein; and the cholesterol in non-high density lipoprotein content, correlating them with the markers: lipoprotein A, apoprotein B and low density lipoprotein cholesterol; using the homogeneous method. A total of 1012 patients were selected, segmented by age, sex and condition of use or inhibition of hepatic cholesterol production. In order to increase the power of this group analysis the exams were separated into subgroups, considering the obtained values and methodologies used; correlating the results. The research was carried out with qualitative and quantitative variables, using nonparametric statistical tests for their comprehension, distribution and grouped analysis. Our results showed evidence that cardiovascular risk is not only associated with the low density lipoprotein cholesterol obtained by Martin's formula, but other variables, in association with the following comparative analyzes: that the use of apoprotein B expands the diagnosis of inclusion of dyslipidemias in 43 % using genderindependent baseline values and with a new monitoring range of 84 mg/dL. That the low density lipoprotein cholesterol obtained by the homogeneous method presents an analytical disagreement at + 3.5% and having a 48% higher diagnostic stratification. In addition, lipoprotein a levels were higher than 30 mg/dL in 26% of the patients, but with a specific prevalence and segmentation in women between the ages of 51 and 60 years, with an apparent disagreement of more than 10 mg/dL when of the comparison of results between the Martin formula and the homogeneous method.
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Sledziecka, Anna Katarzyna. "Covalent lipoprotein(a) assembly : characterization of oxidase activity responsible for catalyzing covalent lipoprotein(a)." Kingston, Ont. : [s.n.], 2008. http://hdl.handle.net/1974/1596.
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Gabel, Brent R. "Analysis of lipoprotein(a) assembly." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ35960.pdf.
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Rip, Jacob. "Lipoprotein lipase, hypertriglyceridemia and atherosclerosis." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2006. http://dare.uva.nl/document/28665.
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Zhang, Liyan. "Lipoprotein lipase - unstable on purpose? /." Doctoral thesis, Umeå : Department of Medical Biosciences, Physiological Chemistry, University of Umeå, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1058.
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Watson, Timothy David George. "Lipoprotein metabolism in the horse." Thesis, University of Glasgow, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335859.
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Gaw, Allan. "Molecular genetics of lipoprotein(a)." Thesis, University of Glasgow, 1995. http://theses.gla.ac.uk/4015/.
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The work presented in this thesis aims to extend our understanding of controlling mechanisms that influence the plasma concentration of lipoprotein(a) [LP(a)]. The techniques of apo(a) genotyping and apo(a) phenotyping are used to study Lp(a) in different ethnic and genetic groups to achieve this end. In chapter 3 the effective use of a commercially available monoclonal antibody is demonstrated. Two primary antibodies were compared and apo(a) isoform analysis was performed using an immunoblotting method. With both monoclonals it was possible to detect 0.05mg. dL-1 Lp(a). Distributions of plasma Lp(a) concentrations exhibit marked inter-racial differences. Apo(a), the unique constituent of Lp(a), is highly polymorphic in length due to allelic variations in the number of kringle 4 (K-4)-encoding sequences. Plasma Lp(a) concentrations are inversely related to the number of K-4 repeats in the apo(a) alleles. To determine the contribution of this length variation to the inter-racial variation in plasma Lp(a) levels, the APO(a) allele size, glycoprotein size, and plasma Lp(a) concentrations in Caucasians, Chinese and African-Americans were compared in chapter 4. Caucasians and African-Americans had very different distributions of plasma Lp(a) concentrations yet there was no significant difference in the overall frequency distributions of their APO(a) alleles. Over the entire size spectrum of apo(a) alleles, the plasma Lp(a) levels were higher in African-Americans that in Caucasians. Conversely, Caucasians and Chinese had similar plasma Lp(a) concentrations, but significantly different APO(a) allele size distributions. Therefore, inter-racial differences in plasma concentrations of Lp(a) are not due to differences in the frequency distributions of APO(a) alleles. The relationship between APO(a) allele size and the presence of detectable plasma apo(a) protein in plasma were also examined. APO(a) alleles associated with no detectable plasma protein were not of uniformly large size, as had been expected, but were distributed over the entire size spectrum. From this analysis, it was concluded that there is no common "null" allele at the APO(a) locus.
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Palm, Wilhelm, Marta M. Swierczynska, Veena Kumari, Monika Ehrhart-Bornstein, Stefan R. Bornstein, and Suzanne Eaton. "Secretion and Signaling Activities of Lipoprotein-Associated Hedgehog and Non-Sterol-Modified Hedgehog in Flies and Mammals." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-180911.
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Hedgehog (Hh) proteins control animal development and tissue homeostasis. They activate gene expression by regulating processing, stability, and activation of Gli/Cubitus interruptus (Ci) transcription factors. Hh proteins are secreted and spread through tissue, despite becoming covalently linked to sterol during processing. Multiple mechanisms have been proposed to release Hh proteins in distinct forms; in Drosophila, lipoproteins facilitate long-range Hh mobilization but also contain lipids that repress the pathway. Here, we show that mammalian lipoproteins have conserved roles in Sonic Hedgehog (Shh) release and pathway repression. We demonstrate that lipoprotein-associated forms of Hh and Shh specifically block lipoprotein-mediated pathway inhibition. We also identify a second conserved release form that is not sterol-modified and can be released independently of lipoproteins (Hh-N*/Shh-N*). Lipoprotein-associated Hh/Shh and Hh-N*/Shh-N* have complementary and synergistic functions. In Drosophila wing imaginal discs, lipoprotein-associated Hh increases the amount of full-length Ci, but is insufficient for target gene activation. However, small amounts of non-sterol-modified Hh synergize with lipoprotein-associated Hh to fully activate the pathway and allow target gene expression. The existence of Hh secretion forms with distinct signaling activities suggests a novel mechanism for generating a diversity of Hh responses.
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Dionne, Carole. "La déficience en lipoprotéine lipase chez les canadiens français : étude spatiale, génétique et généalogique /." Thèse, Québec : Université Laval, École des gradués, 1991. http://theses.uqac.ca.
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Mémoire (M.Sc.)-- Université du Québec à Chicoutimi, 1991."Mémoire présenté pour l'obtention du grade de maître en sciences (M.Sc.)" Ce mémoire a été réalisé à l'UQAC dans le cadre du programme de maîtrise en médecine expérimentale (volet génétique) extensionné de l'Un. Laval à l'UQAC. CaQCU CaQCU Bibliogr.: f. 82-86. Document électronique également accessible en format PDF. CaQCU
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Koska, Juraj, Hussein Yassine, Olgica Trenchevska, Shripad Sinari, Dawn C. Schwenke, Frances T. Yen, Dean Billheimer, Randall W. Nelson, Dobrin Nedelkov, and Peter D. Reaven. "Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes." AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2016. http://hdl.handle.net/10150/614755.
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The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC-III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross-sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT NOW, a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RACED (n = 296), a study of intensive glycemic control and atherosclerosis in type 2 diabetes patients. At baseline, higher relative apoC-(I)II2 and apoC-III2/apoC-III1 ratios were associated with lower triglycerides and total cholesterol in both cohorts, and with lower small dense LDL in the RACED. Longitudinally, changes in apoC-III2/apoC-III1 were inversely associated with changes in triglycerides in both cohorts, and with total and small dense LDL in the RACED. apoC-III2/apoC-III1 was also higher in patients treated with PPAR-gamma agonists and was associated with reduced cardiovascular events in the RACED control group. Ex vivo studies of apoC-III complexes with higher apoC-III2/apoC-III1 showed attenuated inhibition of VLDL uptake by HepG2 cells and LPL-mediated lipolysis, providing possible functional explanations for the inverse association between a higher apoC-III2/apoC-III1 and hypertriglyceridemia, proatherogenic plasma lipid profiles, and cardiovascular risk.
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Wilson, Heather Marion. "High density lipoprotein subspecies and the control of lipoprotein metabolism in relation to coronary heart disease." Thesis, University of Aberdeen, 1990. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU031961.
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The concept that high plasma concentrations of high density lipoproteins (HDL) offers protection against coronary heart disease has been challenged on epidemiological grounds. This dispute may arise as a result of the heterogeneous nature of HDL in which only some subspecies exert a protective function while the major portion has a neutral role. In order to test this hypothesis, the distribution of HDL subfractions in 100 myocardial infarction (MI) survivors was examined within 12 hours of the onset of chest pain and before post-MI changes in lipoproteins occurred. These patients were shown to have a significantly lower percentage distribution of apoprotein E-rich HDL measured by heparin-Sepharose affinity chromatography, and of HDL2b estimated by gradient gel electrophoresis, yet a higher percentage distribution of HDL3c than a similarly sized group of healthy control subjects. At six months post-MI follow-up with an appropriate improvement in lifestyle, as well as therapeutic treatment, there was a significant increase in the percentage distribution of apoprotein E-rich HDL and of HDL2b and a significant decrease in HDL3c, with no alteration in total HDL or any other lipoprotein component. Measurement of these HDL subfractions may thus provide a better indicator of coronary risk than of total plasma cholesterol, which is frequently employed for this purpose, but was found indistinguishable between the two groups in the present study. Such subfractions also provide useful information into the underlying causes of atherosclerosis. The apoprotein E-rich subfraction of HDL which was shown to be reduced in MI survivors, was further separated into several, more discrete subfractions by heparin-Sepharose affinity chromatography, using a judicious choice of eluting solvents. The separated subfractions differed in mean particle diameter and in lipid and apoprotein composition. The fraction designated HDL2b was shown to comprise three main species which may serve different roles in coronary protection.
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Ngqaneka, Thobile. "The impact of Niacin on PCSK9 levels in vervet monkeys (Chlorocebus aethiops)." University of Western Cape, 2020. http://hdl.handle.net/11394/7931.
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Magister Pharmaceuticae - MPharmCardiovascular diseases (CVDs) such as ischaemic heart diseases, heart failure and stroke remain a major cause of death globally. Various deep-rooted factors influence CVD development; these include but are not limited to elevated blood lipids, high blood pressure, obesity and diabetes. A considerable number of proteins are involved directly and indirectly in the transport, maintenance and elimination of plasma lipids, including high and low-density lipoprotein cholesterol (HDL-C and LDL-C). There are several mechanisms involved in the removal of LDL particles from systemic circulation. One such mechanism is associated with the gene that encodes proprotein convertase subtilisin/kexin type 9 (PCSK9), which has become an exciting therapeutic target for the reduction of residual risk of CVDs. Currently, statins are the mainstay treatment to reduce LDL-C, and a need exists to further develop more effective LDL-C-lowering drugs that might supplement statins. This study was aimed at contributing to the generation of knowledge regarding the effect of niacin in reducing LDL levels through PCSK9 interaction.
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Lester, Sandy Marie. "Lipoprotein subclass analysis by immunospecific density." [College Station, Tex. : Texas A&M University, 2008. http://hdl.handle.net/1969.1/ETD-TAMU-3123.
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Neuger, Lucyna. "Aspects on lipoprotein lipase and atherosclerosis." Doctoral thesis, Umeå : Univ, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-564.
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Potts, Jennifer Lucy. "Lipoprotein metabolism in human adipose tissue." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.334875.
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Loughrey, Clodagh Maria. "Lipoprotein oxidation in chronic renal failure." Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318949.
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Sani, Halimah Abdullah. "Mechanisms of control of lipoprotein lipase." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386912.
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Hogg, Neil. "Oxidative modification of low density lipoprotein." Thesis, University of Essex, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316228.
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Le, Riche Mia. "Lipoprotein X : biochemical predictors and detection by non-denaturing polyacrylamide gradient gel electrophoresis." Thesis, Stellenbosch : Stellenbosch University, 2007. http://hdl.handle.net/10019.1/18218.
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Assignment (MMed)--University of Stellenbosch, 2007.ENGLISH ABSTRACT: Lipoprotein X (LpX) is an abnormal cholesterol-containing particle that may be present in the serum of subjects with cholestasis, lecithin:cholesterol acyltransferase (LCAT) deficiency and parenteral nutrition. The biochemistry, metabolism, clinical significance and laboratory analysis of LpX is discussed in this study. This laboratory-based project investigated icteric samples received at the Chemical Pathology laboratory, Tygerberg Hospital, for serum predictors of LpX and the use of a modified non-denaturing polyacrylamide gradient gel electrophoresis system in the detection of LpX. The study showed that the non-denaturing polyacrylamide gradient gel electrophoresis system (2-8%) is a useful test in demonstrating LpX in icteric plasma and has potential for a screening test in LCAT deficiency. Serum concentration of conjugated bilirubin, alkaline phosphatase, gamma glutamyltransferase, free cholesterol, phospholipid, free cholesterol: total cholesterol ratio and conjugated bilirubin: total bilirubin ratio are all good predictors of LpX. The ratio of free cholesterol to total cholesterol (FC/TC > 0.6) was the best predictor of LpX. In the setting of obstructive liver disease LpX is seen in 66% of patients if total cholesterol is > 7.5 mmol/L.
AFRIKAANSE OPSOMMING: Lipoproteien X (LpX) is ‘n abnormale cholesterol-bevattende partikel wat teenwoordig mag wees in die serum van persone met cholestase, lesitien:cholesterol asieltransferase (LCAT) gebrek en parenterale voeding. Die biochemie, metabolisme, kliniese belang en laboratorium analise van LpX word bespreek in hierdie werkstuk. Hierdie laboratorium-gebaseerde projek het geelsugtige monsters ondersoek wat ontvang is by die Chemiese Patologie laboratorium, Tygerberg Hospitaal, vir serum voorspellers van LpX en die gebruik van ‘n gemodifiseerde nie-denaturerende polie-akrielamied gradiënt gel elektroforese sisteem in die demonstrasie van LpX. Die bevindinge was dat die nie-denaturerende polie-akrielamied gradient gel elektroforese sisteem (2-8%) is ‘n nuttige toets om LpX te demonstreer in geelsugtige plasma en het potensiaal as ‘n siftingstoets in LCAT gebrek. Serum konsentrasie van gekonjugeerde bilirubien, alkaliese fosfatase, gamma glutamieltransferase, vry cholesterol, fosfolipied, vry cholesterol:totale cholesterol verhouding en gekonjugeerde bilirubien:totale bilirubien verhouding is alles goeie voorspellers van LpX. Die verhouding van vry cholesterol tot totale cholesterol (VC/TC > 0.6) was die beste voorspeller van LpX. In gevalle van obstruktiewe lewersiekte word LpX gesien in 66% van pasiente as die totale cholesterol meer as 7.5 mmol/l is.
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Hassel, Craig Alan. "LIPOPROTEIN RECEPTORS IN COPPER-DEFICIENT RATS: IN VITRO BINDING OF HIGH DENSITY LIPOPROTEIN SUBFRACTIONS TO LIVER MEMBRANES." Diss., The University of Arizona, 1986. http://hdl.handle.net/10150/183955.
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Three studies were conducted to determine whether the elevated plasma and HDL cholesterol levels observed in copper-deficient rats could be explained by the interaction of ¹²⁵I-HDL subfractions with liver membrane preparations in vitro. Rats from all studies were randomly divided into two dietary treatments, copper-deficient and adequate (0.7 mg and 8.0 mg Cu/kg diet, respectively). Deionized water and diet were provided ad libitum. After eight weeks, rats were exsanguinated, membranes prepared from livers, and plasma high density lipoproteins (HDL) isolated by ultracentrifugation and agarose column chromatography. Heparin-Sepharose affinity chromatography was used to isolate specific subfractions of HDL. The HDL subfractions derived from rats of each dietary treatment were iodinated and bound to either crude liver membranes or purified liver plasma membranes prepared from rats of both treatment groups. Total binding data and computer derived estimates (K(d) and B(max)) were used to compare differences between treatments. Binding data from all experiments conformed to a one-site model. In all cases, binding was saturable and EDTA and pronase insensitive. Treatment differences were observed in Study I (¹²⁵I-apo E-free HDL binding to crude liver membranes). Significantly lower total binding and B(max) were observed when lipoproteins and membranes from copper-deficient animals were used in the assay. Competition experiments from Studies II and III demonstrate that the different HDL subfractions competed effectively with one another for binding sites, indicating that apo E is not a determinant in binding of rat ¹²⁵I-HDL subfractions to purified liver plasma membranes.
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Humphries, William Henry IV. "Intracellular degradation of low-density lipoprotein probed with two-color fluorescence microscopy." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/42832.
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The vesicle-mediated degradation of low-density lipoprotein (LDL) is an essential cellular function due to its role in cellular biosynthesis of membranes and steroids. Using multi-color single particle tracking fluorescence microscopy, the intracellular degradation of LDL was probed in live, intact cells. Unique to these experiments is the direct observation of LDL degradation using an LDL-based probe that increases fluorescence intensity upon degradation. Specifically, individual LDL particles were labeled with multiple fluorophores resulting in a quenched fluorescent signal. The characteristics of the vesicle responsible for degradation were determined and the vesicle dynamics involved in LDL degradation were quantified. Visualization of early endosomes, late endosomes and lysosomes was accomplished by fluorescently labeling vesicles with variants of GFP. Transient colocalization of LDL with specific vesicles and the intensity of the LDL particle were measured simultaneously. These studies, which are the first to directly observe the degradation of LDL within a cell, strive to completely describe the endo-lysosomal pathway and quantify the dynamics of LDL degradation in cells.
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Huang, Annong. "Effects of Oxidized Low Density Lipoprotein on Nitric Oxide Production in Macrophages." Digital Commons @ East Tennessee State University, 1997. https://dc.etsu.edu/etd/2924.
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The effects of oxidatively modified low density lipoprotein (oxLDL) on atherogenesis may be partly mediated by alterations in nitric oxide (NO) production by macrophages. A major goal of this study was to identify the lipid components in oxLDL modulating NO production. The effect of a water soluble antioxidants (N-acetylcysteine) and lipid soluble antioxidant (alpha-tocopherol) on NO production in macrophages was also determined. A second goal was to determine if the effects of oxLDL occurred at the transcriptional level. Human LDL was oxidized using an azo-initiator 2,2$\sp\prime$-azobis (2-amidinopropane) HCI (ABAP). OxLDL markedly decreased the production of NO in LPS stimulated RAW264.7 macrophages. This inhibition depended on the levels of LOOH formed in oxLDL and was not due to oxLDL cytotoxicity. In contrast, acetylated LDL (AcLDL) and native LDL showed only minor inhibition. Lipid hydroperoxides (LOOH) and lysophosphatidylcholine (lysoPC) are the primary products formed during LDL oxidation. 13-Hydroperoxyl octadecadienoic acid (13-HPODE) markedly inhibited NO production, whereas lysoPC showed only slight inhibition. Furthermore, the effects of 13-HPODE and lysoPC did not require their uptake in an AcLDL carrier. Pre-treatment of macrophages with alpha-tocopherol attenuated the inhibition due to oxLDL. Similarly, pre-treatment with N-acetylcysteine attenuated the inhibition caused by oxLDL or 13-HPODE. OxLDL was found to decrease iNOS protein and mRNA levels in RAW264.7 macrophages induced by LPS. The activation of NF-$\kappa$B was slightly suppressed after 45 minutes of treatment. 13-HPODE showed much stronger reduction of iNOS protein levels than lysoPC. These results suggest that oxLDL may inhibit NO production in macrophages at transcriptional level. 13-HPODE is likely to be the most important lipid component in oxLDL for the inhibitory effect. Antioxidants were found to preserve NO production in macrophages treated with either oxLDL or 13-HPODE. The physiological consequences of decreased NO production in macrophages caused by oxLDL are discussed with respect to atherosclerosis.
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Mohiman, Niloofar. "Étude de la biogénèse des lipoprotéines chez Corynebacterium glutamicum." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114865.
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En raison de leur contribution à la virulence bactérienne, les lipoprotéines et les membres de la voie de biogenèse des lipoprotéines représentent des cibles prometteuses pour la recherche de nouveaux antibiotiques. À la suite de translocation à travers la membrane interne la future lipoprotéine ancrée dans la membrane par l’intermédiaire de son peptide signal, va subir en premier lieu l’addition de sn-1,2-diacylglyceryle sur la fonction sulfhydryle de la future cystéine N-terminale de la lipoprotéine mature. Cette modification est catalysée par Lgt (prolipoprotéin diacylglycérol transférase) avant même que le peptide signal de la lipoprotéine ne soit clivé par Lsp (lipoprotéine signal peptidase). L’action de la peptidase permet de libérer l’amine terminale de la cystéine qui pourra alors, chez les bactéries à Gram-négatif, être acylée par Lnt (lipoprotéin aminoacyl transférase). La présence d’un apolipoprotéine N-acyltransférase (Ppm2-Ms) impliquées dans la N-acylation de LppX a récemment été montrée chez M. smegmatis. Ppm2-Ms fait partie de l'opéron ppm dans laquelle ppm1, une synthase polyprénol-monophosphomannose, a été révélée essentielle dans la synthèse lipoglycans mais dont la fonction dans la biosynthèse des lipoprotéines est totalement inconnue. Afin de clarifier le rôle de l'opéron ppm dans la biosynthèse des lipoprotéines, nous avons étudié les modifications post-traductionnelles de deux modèles (lipoprotéines AmyE et LppX) dans les mutants Δppm1 et Δppm2 chez C. glutamicum.Nos résultats montrent que les deux lipoprotéines modèles sont ancrées dans la membrane et que leurs extrémités N-terminales sont N-acylés par Ppm2-Cg. Le peptide N-teminal acylé de LppX a été également modifié par des groupements d'hexose. Cette O-glycosylation est localisée dans le peptide N-terminal de LppX mais absente dans le mutant Δppm1. Tandis compromise en l'absence de Cg-PPM2, O-glycosylation LppX pourrait être rétabli lorsque Cg-PPM1, Cg-PPM2 ou l'homologue Mt-ppm1 de M. tuberculosis a été surexprimée. Ensemble, ces résultats montrent pour la première fois que Ppm1-Cg (Ppm synthase) et Ppm2-Cg (Lnt) fonctionnent dans une voie de biosynthèse commune dans laquelle la glycosylation et la N-acylation des lipoprotéines sont étroitement couplésDue to their contribution to bacterial virulence, lipoproteins and members of the lipoprotein biogenesis pathway represent potent drug targets. Following translocation across the inner membrane, lipoprotein precursors are acylated by lipoprotein diacylglycerol transferase (Lgt), cleaved off their signal peptides by lipoprotein signal peptidase (Lsp) and, in Gram-negative bacteria, further triacylated by lipoprotein N-acyl transferase (Lnt). The existence of an active apolipoprotein N-acyltransferase (Ms-Ppm2) involved in the N-acylation of LppX was recently reported in M. smegmatis. Ms-Ppm2 is part of the ppm operon in which Ppm1, a polyprenol-monophosphomannose synthase, has been shown to be essential in lipoglycans synthesis but whose function in lipoprotein biosynthesis is completely unknown. In order to clarify the role of the ppm operon in lipoprotein biosynthesis, we investigated the post-translational modifications of two model lipoproteins (AmyE and LppX) in C. glutamicum ∆ppm1 and ∆ppm2 mutants. Our results show that both proteins are anchored into the membrane and that their N-termini are N-acylated by Cg-Ppm2. The acylated Ntermina peptide of LppX was also found to be modified by hexose moieties. This O-glycosylation is localized in the N-terminal peptide of LppX and disappeared in the ∆ppm1 mutant. While compromised in the absence of Cg-Ppm2, LppX Oglycosylation could be restored when Cg-Ppm1, Cg-Ppm2 or the homologous Mt-Ppm1 of M. tuberculosis was overexpressed. Together, these results show for the first time that Cg-Ppm1 (Ppm synthase) and Cg-Ppm2 (Lnt) operate in a common biosynthetic pathway in which lipoprotein N-acylation and glycosylation are tightly coupled
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Ramsay, Amanda. "The role of high density lipoprotein subspecies in the control of lipoprotein metabolism in relation to clinical disorders." Thesis, University of Aberdeen, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338398.
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In order to examine the role of HDL in the control of lipoprotein metabolism, the levels of HDL subspecies, other lipoproteins, apolipoproteins and fatty acids were measured in four groups of subjects presenting clinical disorders which were possibly related to their lipid profiles. (1) A monoclonal antibody was raised against apolipoprotein A-I allowing the development of an ELISA. (2) In a comparison of 43 angina patients and 61 healthy control subjects, the levels of HDL2, HDL2b and HDL2a were lower in the angina group and this was compensated for by an increase in levels of HDL3b and HDL3c. Plasma triglyceride and VLDL-cholesterol concentrations were higher in the angina group possibly giving rise to the low levels of HDL2 subspecies by their effect on HDL particle conversion. The subspecies HDL2b has been implicated in reverse cholesterol transport. (3) In a study of nine hypertriglyceridaemic subjects and 23 healthy controls there was a lower concentration of HDL2b, HDL2a and LDL-cholesterol and a higher concentration of HDL3b and VLDL-cholesterol in the hypertriglyceridaemic group. This was possibly indicative of reduced LPL activity. The resulting high levels of plasma triglyceride are known to favour the conversion of HDL2 to HDL3. These results suggest that hypertriglyceridaemic patients have a reduced ability to eliminate surplus cholesterol by reverse cholesterol transport and would therefore be at increased risk of atherosclerosis. (4) In a study of 17 violent offenders and 25 control subjects, the HDL subfraction HDL3a was higher in the offenders. The levels of the apolipoproteins E and A-IV were higher in the offender group perhaps having a role in the repair of damaged nervous tissue.
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Niu, Youguo. "Cardiac Lipoprotein Metabolism in Health and Diabetes." Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.491543.
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Triacylglycerols (TAG)-rich lipoproteins (TGRLPs), i.e. very-low-density lipoprotein (VLDL) and chylomicrons (CM), are believed to be important substrates for heart to produce ATP and to incorporate constituents of cardiomyocyte membranes. However, cardiac utilisation of TGRLPs has not been fully understood. Therefore, the aims of the study were to investigate metabolism of TGRLPs by the isolated 'working' rat heart under physiological and diabetic conditions. Radiolabelled VLDL and CM particles were prepared by an extended liver perfusion and a thoracic duct cannulation technique respectively. Streptozotocin (STZ)-treated rats and Zucker Diabetic Fatty (ZDF) rats were used as type 1 and 2 diabetic animal models. Under physiologically moderate workload conditions, both VLDL and CM could maintain the isolated heart in good 'working' performance. Lipoprotein lipase (LPL)mediated hydrolysis was the principal mechanism for heart to take up VLDL and CM. Receptor-mediated endocytosis, although less quantitatively important regarding the uptake of TGRLPs, was a mechanism which preferentially 'channelled' TAG assimilated towards oxidation rather than esterification. CM was a preferable substrate for heart to use, mainly as an energy source. VLDL, however, may have a different role in cardiac lipoprotein metabolism. Only about half of VLDL-TAG assimilated was oxidised and the oxidation rate of VLDL-TAG was markedly lower than that ofCM-TAG. In diabetic hearts, heparin-releasable LPL activity was significantly increased. But surprisingly, no significant change in TAG uptake was found in diabetes, although a slight increased trend was shown in ZDF rats. Significantly higher TAG oxidation rates and lower glucose oxidation rates were demonstrated in diabetic hearts, supporting the shift of cardiac substrate utilisation from glucose to lipids (not only non-esterified fatty acid but also TAG) in diabetes. The proportion of VLDL-TAG oxidised in diabetes was much higher than that in control, suggesting that VLDL could act as an extracellular energy store for hearts. The total tissue lipid esterification was unchanged but an enhanced TAG accumulation was found in STZtreated hearts, although cardiac performance was maintained. The effects of diabetic lipoproteins on metabolism were also demonstrated, possibly due to changes in lipoprotein particle composition, which was found to be disturbed in diabetes. These results suggest that VLDL and CM have a different metabolic role in the heart. The importance of the utilisation of these lipids was also confirmed by the findings in diabetes. Therefore, manipulation of lipoproteins and their utilisation may be important therapeutically.
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Breznan, Dalibor. "High-density lipoprotein metabolism in the kidney." Thesis, University of Ottawa (Canada), 2002. http://hdl.handle.net/10393/6120.
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The kidney is believed to play a major role in the clearance and re-absorption of high density lipoprotein (HDL) particles from the blood. Experiments were undertaken to explore the specific sites of renal HDL metabolism in vivo and to investigate in vitro the factors that regulate the renal re-absorption of HDL by HKC-8 human proximal tubule (PT) cells. Perfusion of a rabbit renal artery with [3H]cholesteryl ester (CE) and 125I-protein labeled HDL particles showed that the kidneys are capable of filtering both apolipoprotein A-I (apoA-I) and whole HDL. A fluorescent microscopic study with the HKC-8 cells showed that the PT cells can bind and take up HDL particles. (Abstract shortened by UMI.)
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Herd, Sara L. "Exercise, postprandial lipaemia and lipoprotein lipase activity." Thesis, Loughborough University, 1997. https://dspace.lboro.ac.uk/2134/28431.
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Impaired clearance of triacylglycerol-rich lipoproteins contributes to atherogenesis. It can be argued that exercise may decrease the risk of atherosclerotic diseases through its potential to improve the metabolic capacity for triacylgycerol and hence, clearance of triacylglycerol-rich lipoproteins. The investigations described in this thesis focused on the influence of exercise on postprandial lipid and lipoprotein metabolism.
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Puckey, Loretto Helena. "The genetic regulation of lipoprotein (a) concentration." Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289825.
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Gopalraj, Rangaraj K. "LOW DENSITY LIPOPROTEIN RECEPTOR AND ALZHEIMERS DISEASE." UKnowledge, 2009. http://uknowledge.uky.edu/gradschool_diss/697.
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Since apoE allele status is the predominant Alzheimers disease (AD) genetic risk factor, functional single nucleotide polymorphisms (SNPs) in brain apoE receptors represent excellent candidates for association with AD. Therefore, three low density lipoprotein receptor (LDLR) SNPs were evaluated by TaqMan allelic discrimination assays for association with AD and I found that certain haplotypes alter the odds of AD. A SNP within LDLR exon 12, rs688, was identified in silico as neutralizing a putative exon splicing enhancer (ESE). Since LDLR is a major apoE receptor in the brain, I hypothesized that rs688 modulates LDLR splicing in neural tissues and associates with AD. To evaluate this hypothesis, I analyzed splicing patterns in human hippocampus samples and established that this SNP was associated with significantly decreased LDLR exon 12 splicing efficiency when the minor allele T is present in vivo. Lastly, I evaluated whether rs688 associates with AD by genotyping DNA from the Religious Orders Study (ROS) series. The rs688T/T genotype was associated with increased AD odds in males, but not in females, in a dataset consisting of 1,457 men and 2,055 women drawn from three case-control series. The rs688T/T genotype was associated with increased AD odds in males (recessive model, odds ratio (OR) of 1.49, 95% confidence interval (CI) of 1.13- 1.97, uncorrected p=0.005), but not in females. In summary, these studies identify a functional apoE receptor SNP that is associated with AD in a sex-dependent fashion.
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朱瑞中 and Sui-chung Chu. "Regulation of lipoprotein uptake in mammalian cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31969707.
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McDowell, Andrew. "Modifications of low density lipoprotein and atherosclerosis." Thesis, Queen's University Belfast, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314171.
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Oliver, Jason David. "Aspects of control of lipoprotein lipase expression." Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335174.
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Fielding, Barbara Ann. "Studies of the action of lipoprotein lipase." Thesis, Manchester Metropolitan University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361176.
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Chu, Sui-chung. "Regulation of lipoprotein uptake in mammalian cells." Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B22088982.
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Karnas, Kimberly Joy. "Lipoprotein biosynthesis: Examination of the lipidation process." Diss., The University of Arizona, 2001. http://hdl.handle.net/10150/279787.
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Lipoproteins, protein-lipid complexes that have a polar exterior and a non-polar interior, have been found in many vertebrate and insect species, and their basic structure and function appear to be conserved. They facilitate the intercellular transport of hydrophobic lipids through aqueous media. Their synthesis requires an unusual process referred to as lipidation, whereby lipids are added to the protein component of the lipoprotein. Lipidation is thought to occur during or immediately following translation of these proteins, but how this process occurs is unknown. Of particular interest is the extent to which the protein sequence of the apoproteins drives lipidation and the level of involvement of other proteins in this process. In this project, lipidation was studied by expressing the apolipoproteins from the tobacco hornworm, Manduca sexta, in two different expression systems. The first used budding yeast, Saccharomyces cerevisiae , to both determine the ability of unicellular organisms to produce lipoproteins and examine the role that the known secretory pathway for soluble proteins plays in lipoprotein biosynthesis. The second used Drosophila Schneider 2 cells to begin to examine the apolipoprotein sequence for regions that are crucial to lipoprotein biosynthesis. The yeast expression system revealed that unicellular organisms are capable of expressing, lipidating, and secreting M. sexta apolipoproteins. This is first demonstration of any apolipoprotein being expressed in a unicellular organism, and represents a major finding, as unicellular organisms have no need for a particle that functions in intercellular transport. A second major finding in this project is that lipophorin production occurs in the absence of the full apoLp-I sequence. This finding was true for both expression systems, and indicates that the lipidation code resides within the first 45% of the precursor protein sequence. Furthermore, deletion analysis has revealed that removal of any portion of the apoLp-II sequence prevents expression of the apolipoprotein. Taken together, these experiments indicate that all of the information required to make a lipoprotein is included in the apoLp-II sequence.
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George, Ian M. R. "Immunolocalization and quantitation of avian lipoprotein lipase." Thesis, University of Edinburgh, 1993. http://hdl.handle.net/1842/28092.
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The overall aim of the project was to investigate the pools of LPL activity that exist within chicken tissues in vivo. Polyclonal and monoclonal anti-chicken LPL antibodies were produced using highly purified chicken adipose tissue LPL as an immunogen. An attempt was made to measure LPL at the luminal surface of the capillary endothelium of individual tissues using an iodinated anti?chicken LPL monoclonal antibody, injected intravenously, in vivo. However, the technique was not successful because high levels of specific antibody binding were not achieved. Heparin-release studies using the isolated perfused heart model system found significant species differences, between rats and chickens, in the regulation of heparin-releasable LPL in response to fasting. The low percentage of heparin-releasable LPL activity observed in chickencardiac tissue corresponded to the relatively low accumulation oftriacylglycerol NEFA by the chicken muscular tissues by comparisonwith adipose tissue, following the intravenous injection of [^4C]-VLDL invivo. Using anti-chicken LPL antibodies immunocytochemical studies on a variety of chicken extrahepatic tissues showed the enzyme to be located predominantly extracellularly, at the basement membrane of the tissue parenchymal cells and in association with the interstitial capillary elements. Image-analysis was used to quantify the pools of enzymeassociated with these compartments in chicken cardiac tissue. In chicken bone marrow LPL was found in association with the adipocytes and vascular elements of the marrow mass, with a lack of enzyme associated with the haematopoietic cells. Immunocytochemical techniques were also used to investigate the tissue specific developmental changes which occur in the distribution of LPL during the growth and maturation of the heart and liver of the embryonic chicken. The present study has identified several pools of LPL within chicken tissues and proposed that the transportation of enzyme from the interstitial capillary elements to the luminal endothelial surface may play a role in the regulation of functional LPL activity in chicken tissues.
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Blain, Jean-François. "Modulation of lipoprotein metabolism in response to brain inury and Alzheimer's disease : roles for apolipoprotein E4 and lipoprotein lipase." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85886.
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From the association of the epsilon4 allele of apolipoprotein (apo) E with Alzheimer's disease (AD) to the more recent reports of reduced risks of developing the disease when taking cholesterol lowering agents, links seem to point for a central role for lipoprotein metabolism in the AD brain. While the association with apoE4 is the strongest and most reproduced risk factor for AD, roles for other proteins involved in lipoprotein metabolism in the periphery have not been thoroughly investigated.Using the entorhinal cortex lesion (ECL) paradigm in human apoE-targeted replacement mice we examine whether apoE4 has effects on reactive synaptogenesis in the absence of the concentration bias observed in human and how these effects are mediated. In a second study, again using the ECL model, we investigate the role of lipoprotein lipase (LPL) in the brain in response to injury. Finally, we study the effect of intronic polymorphisms of the LPL on the risk and severity of AD.
The results show that mice expressing apoE4 have impaired astroglial organization resulting from an exacerbated inflammatory state and culminating into reactive synaptogenesis impairment. We also observe isoform-specific tau phosphorylation and beta-amyloid (Abeta) accumulation. Furthermore, we report that LPL plays a role in the degeneration phase following ECL. We propose that it is involved in the recycling of lipids together with the glial-specific proteoglycan syndecan-4. Finally we report associations between LPL polymorphisms and AD risk and severity. Since the polymorphisms associate with increased expression of LPL in AD brain as well as with increased senile plaque number, we propose that LPL may be involved in amyloid clearance and deposition.
Taken together these results confirm the importance of lipoprotein metabolism in AD as apoE and LPL are both involved in maintaining cholesterol homeostasis in the brain and also both participate in Abeta metabolism.
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Khan, Tina. "Clinical outcomes, perfusion and vascular function in patients with refractory angina and raised lipoprotein (a), treated with lipoprotein apheresis." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/51551.
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Background: Angina which is refractory to conventional medical therapy and revascularisation is challenging to manage and novel therapeutic options are needed. Raised lipoprotein(a) is common in refractory angina and is an independent cardiovascular risk factor that can be reduced by lipoprotein apheresis. To date there is no randomised controlled data assessing the clinical benefit of lipoprotein apheresis in patients with refractory angina and raised lipoprotein(a). Methods: We conducted a randomised controlled trial in 20 patients with refractory angina and raised lipoprotein(a), with three months of blinded weekly lipoprotein apheresis or sham, followed by crossover. The primary endpoint was change in quantitative myocardial perfusion reserve (MPR) assessed by cardiovascular magnetic resonance. Secondary endpoints included measures of atheroma burden, exercise capacity, symptoms and quality of life. Results: The primary endpoint MPR increased by 0.47 [95% CI, 0.31 to 0.63] from 1.45±0.36 to 1.93±0.45 following apheresis, but decreased during sham by -0.16 [95% CI, -0.33 to 0.02] from 1.63±0.43 to 1.47±0.30; yielding a net treatment increase of 0.63 [95% CI 0.37 to 0.89; p < 0.001 between groups]. Median total carotid wall volume (mm3) reduced during apheresis from 2482 [IQR 1910, 2836] before apheresis to 2251 [IQR 1719, 2437] after apheresis, but increased from 2342 [IQR 1997, 2644] pre-sham to 2455 [IQR 2166, 2831] post-sham (p < 0.001 between groups). The Six Minute Walk Test (6MWT) distance(m) improved by a median value of 70.5[IQR 41.5,105.5]; there was no change in the sham arm (P=0.001 between groups). Significant improvements were also demonstrated in 4 of 5 domains of the Seattle Angina Questionnaire (all p < 0.02 between groups) and quality of life physical component summary by the Short Form 36 Survey (p=0.001 between groups). Conclusions: Lipoprotein apheresis is an effective novel treatment option for patients with refractory angina and raised lipoprotein(a) improving myocardial perfusion, atheroma burden, exercise capacity and symptoms.
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Cavalcante, Marcela Frota. "Efeito da imunização passiva com fragmentos variáveis de cadeia única anti-LDL eletronegativa na aterosclerose experimental." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/9/9136/tde-07032013-162526/.
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A aterosclerose é uma doença crônico-inflamatória multifatorial com o envolvimento do sistema imunológico, sendo o resultado da interação de diferentes elementos celulares. A lipoproteína de baixa densidade eletronegativa [LDL(-)], capaz de induzir o acúmulo de ésteres de colesterol em macrófagos e a subsequente formação de células espumosas, desempenha um papel-chave na doença. Anticorpos recombinantes têm sido gerados nas últimas décadas, como o scFv (single chain fragment variable), com o intuito de serem utilizados como uma novas alternativas de prevenção para o surgimento da lesão. Diante do papel da LDL(-) na aterosclerose, este projeto avaliou o efeito da imunização passiva de camundongos LDLr-/-- com scFv anti-LDL(-) em solução e scFv anti-LDL(-) conjugado a nanocápsulas, em relação ao desenvolvimento e progressão da aterosclerose. Após obtenção do scFv e sua conjugação à nanocápsulas (NC-scFv), ensaios in vitro determinaram a diminuição da captação de LDL(-) em macrófagos tratados com o scFv 2C7 anti-LDL(-) em solução. No entanto, o tratamento com NC-scFv promoveu o aumento da internalização de LDL(-) em relação ao controle, possivelmente por um mecanismo de endocitose mediada por receptor específico. Estudos in vivo determinaram que camundongos LDLr-/- com idade entre 2 e 3 meses tratados com o scFv em solução apresentaram menor área de lesão aterosclerótica (p<0,05) quando comparados ao controle e que animais com 3 a 4 meses de idade tratados com NC-scFv demonstraram uma tendência à diminuição do mesmo parâmetro. Na análise da expressão de proteínas por imunohistoquímica, ambos os grupos tratados com scFv 2C7 anti-LDL(-) em solução e NC-scFv demostraram redução significativa da expressão dos receptores CD14 e TLR-4 no local da lesão. Esse achado tem grande importância, uma vez que dados da literatura apresentam ambos os receptores como possíveis candidatos ao reconhecimento da LDL(-). Diante dos dados obtidos, o estudo evidenciou a eficácia do scFv 2C7 anti-LDL(-) em solução e da formulação NC-scFv no contexto da aterosclerose, possibilitando a sua utilização como estratégias terapêuticas na intervenção precoce para prevenir o desenvolvimento e a progressão da doença.Atherosclerosis is a chronic inflammatory multifactorial disease related to the immune system and being the result of interaction of different cellular elements. The electronegative LDL, since the changes undergone by this particle are able to induce the accumulation of cholesterol esters in macrophages and the subsequent formation of foam cells, plays a key role in atherosclerosis. Recombinant antibodies have been generated in recent decades, such as scFv, (single chain fragment variable), and they may be used as a new alternative treatment for atherosclerosis treatment or prevention. Considering the role of LDL(-) in atherosclerosis, this project evaluated the effects of the treatment with anti-LDL(-) scFv 2C7 solution and anti-LDL(-) scFv conjugated to nanocapsules as a passive immunization strategy on atherosclerosis induced in LDL receptor knockout mice. After obtaining the anti-LDL(-) scFv 2C7 solution and its conjugation to nanocapsules (NC-scFv), in vitro tests led to the decrease in LDL(-) uptake in macrophages treated with anti-LDL(-) scFv 2C7. However, the treatment of macrophages with NC-scFv promoted increased internalization of LDL(-) as compared to control, possibly due to a mechanism of specific receptor-mediated endocytosis. In vivo studies have determined that LDLR-/- mice aged 2 and 3 months treated with anti-LDL(-) scFv 2C7 solution showed less atherosclerotic lesion area (p <0.05) compared to control and animals aged 3 to 4 months treated with NC-scFv showed a decreasing tendency of the same parameter. In the analysis of protein expression by immunohistochemistry, both groups treated with anti-LDL(-) scFv 2C7 solution and NC-scFv showed significant reduction of CD14 receptor expression and TLR-4 at the lesion site. This finding is of great importance, since the literature has both receptors as candidates for recognition of the LDL(-). From the data obtained, the study demonstrated the efficacy of treatments anti-LDL(-) scFv 2C7 in solution and NC-scFv in the context of atherosclerosis, enabling their use as therapeutic strategies in the early intervention to prevent the development and progression of the disease.
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Henriquez, Ronald Rene. "Fluorometric sedimentation equilibrium for lipoprotein sub-class analysis." Thesis, [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-2027.
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del, Bas Prior Josep Maria. "Modulation of hepatic lipoprotein metabolism by dietary procyanidins." Doctoral thesis, Universitat Rovira i Virgili, 2007. http://hdl.handle.net/10803/8662.
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INTRODUCTIONDuring the past decade, Nutrition research has been subjected to a shift of focus, from epidemiology and physiology to the comprensión of the molecular basis of nutrients actions.
Thus, the new "-omics" disciplines transcriptomics, proteomics or metabolomics, provide the tools to understand the molecular mechanisms involved in the modulation of gene expression by nutrients. The study of the beneficial properties of wine procyanidins has not avoided this shift of focus. Thus, from the initial studies which defined the "French paradox", to nowadays, a wide array of studies have been focused in defining the properties of the non-alcoholic components of red wine, mainly flavonoids, a family of polyphenolic compounds. The objectives of this thesis have been to define the molecular mechanisms by which grape procyanidins modulate the hepatic metabolism of lipoproteins, reducing the risk of cardiovascular disease and other pathologies which basis is found in the dysregulation of the lipoprotein metabolism.
SUMMARY
In the present thesis, the effect of procyanidins in the hepatic lipoprotein metabolism has been studied. With this objective, HepG2, HeLa and CV-1 cells have been used as invitro models. In vivo studies have been performed in Wistar rats and C57BL6 mice, wild-type and transgenic mice lacking SHP (NR0B2) and FXR (NR5H1).
RESULTS
1. Procyanidins improve plasma lipid profile in the postprandial phase in rats. A single oral dose of procyanidins decreases plasma triglycerides and ApoB levels to 50% of control values. In addition LDL-Cholesterol is significantly reduced, thus improving the atherosclerotic risk index.
2. Procyanidins display a triglyceride-lowering effect both in vivo and in vitro. In rat and mouse, procyanidin treatment triggers a hypotriglyceridemic response. In HepG2 cultures, procyanidins down-regulate the secretion of triglycerides and ApoB, thus showing that these flavonoids act directly on hepatic cells. This fact strongly suggests that, in vivo, a direct action of procyanidins on the liver contributes to their hypotriglyceridemic response.
3. Nuclear receptor Small Heterodimer Partner (SHP) is a target of procyanidins in hepatic cells. Procyanidins modulate the expression of SHP, rapidly increasing its expression in rat liver as well as in HepG2 cultured cells.
4. SHP mediates the triglyceride-lowering activity of procyanidins in vitro and in vivo. When SHP expression is silenced in HepG2 or abolished in SHP-null mice, procyanidins lose their hypotriglyceridemic activity. In contrast, in SHP-silenced HepG2 cells, procyanidins are still able to reduce apoB secretion. Hence, procyanidins reduce triglyceride via a SHP-dependent mechanism, whereas they reduce apoB in a SHPindependent manner.
5. Nuclear receptor Farnesoid X Receptor (FXR) is an essential mediator of the hypotriglyceridemic action of procyanidins upstream SHP. Oral gavage of procyanidins to FXR-null mice have not a hypotriglyceridemic effect. Moreover, luciferase based in vitro assays showed that procyanidins increase the transcriptional activity of FXR. Thus, FXR is an essential component of the signalling pathway used by procyanidins to elicit the triglyceride lowering effect.
6. Key genes of the inflammation process are targets of procyanidins in liver, in the postprandial phase. Oral administration of procyanidins to rats rapidly downregulates the expression, in liver, of transcription factor Egr1, a mediator of the hepatic inflammatory response, and several acute-phase proteins, namely haptoglobin, fibrinogen B and alpha-1 antitrypsin. In addition, expression of DUSP6, a component of the ERK1/2 subfamily of MAPK, is repressed by this treatment. Nfkbia, a repressor of NF-kB activity, is overexpressed upon procyanidin treatment. This expression pattern strongly suggests that procyanidins attenuate the pro-inflammatory state associated to the postprandial phase.
INTRODUCCIÓN
Durante la pasada década, la investigación en nutrición se ha visto sujeta a un cambio en sus objetivos, pasando de los estudios basados en la fisiología y la epidemiología a la comprensión de las bases moleculares implicadas en las acciones biológicas de los nutrientes. Así, las nuevas disciplinas, como la biología molecular o las "-omics", transcriptómica, proteómica o metabolómica, proporcionan las herramientas para el estudio de los mecanismos moleculares implicados en la modulación génica por nutrientes.
El estudio de las propiedades beneficiosas del vino no ha evitado este cambio de foco. Así, desde los primeros estudios que definieron la "paradoja francesa", hasta la actualidad, una ámplia gama de estudios se han dedicado a definir las propiedades de los componentes no alcohólicos del vino, mayoritariamente, los Flavonoides, una familia de compuetos polifenólicos. El objetivo de esta tesis ha sido definir los mecanismos moleculares mediante los cuales las procianidinas de uva modulan el metabolismo de lipoproteínas en el hígado, disminuyendo así el riesgo cardiovascular y diferentes patologías cuya base se encuentra en la desregulación del metabolismo lipoproteico.
MEMORIA
Durante esta tesis se ha estudiado el efecto de las procianidinas sobre el metabolismo lipoproteico en el hígado. Con este objetivo se han usado líneas celulares como modelo in vitro, tanto hepatocitos (HepG2) como líneas accesorias (HeLa y CV-1). Como modelos para el estudio de las procianidinas in vivo se han usado ratas de la cepa Wistar y ratones de la cepa C57BL6, tanto wild-type como dos líneas de transgénicos, Knockout para SHP (NR0B2) y FXR (NR5H1).
RESULTADOS
Se han obtenido los siguientes resultados:
Las procianidinas de uva disminuyen los niveles de lipoproteínas ricas en triglicéridos, así como mejoran los índices de riesgo cardiovascular en ratas.
Estos efectos se deben a la modulación de la expresión génica en el hígado, tejido adiposo y músculo entre otras acciones.
El mecanismo por el cual las procianidinas disminuyen las lipoproteínas ricas en triglicéridos ha sido estudiado in Vitro (HepG2) e in vivo (C57BL6 wild-type y knockout para SHP). Se han definido dos mecanismos principales. El primero implica la señalización de las procianidinas por una vía dependiente de SHP (Small heterodimer partner, NR0B2), un receptor nuclear. El segundo mecanismo es independiente de SHP e inhibe la expresión de MTP (enzima controlador de la síntesis de lipoproteínas) y consecuente secreción de un menor número de lipoproteínas de muy baja densidad (VLDL).
Por encima de SHP, se ha definido FXR (Farnesoid X receptor) como sensor de las procianidinas mediante el uso de ratones C57BL6 KO para FXR y sistemas reporter basados en luciferasa. Estableciendo que el mecanismo de señalización de las procianidinas pasa por FXR, que a su vez induce la expresión de SHP y este inhibe la expresión de SREBP1, factor de transcripción clave para la síntesis de lípidos, disminuyendo así la cantidad de lípidos hepáticos y, consecuentemente, la secreción de lipoproteínas.
DISCUSIÓN
La modulación del metabolismo de lipoproteínas es el principal objetivo para el tratamiento de las diferentes patologías relacionadas con dislipemias. Así, la definición de las procianidinas de uva como agentes hipolipidémicos, las convierte en un componente de la dieta de alta importancia para prevenir y mejorar una ámplia gama de patologías, desde la aterogénesis hasta otros estados metabólicos alterados, causantes de la resistencia a la insulina o el síndrome metabólico.
Por otro lado, el establecimiento de los mecanismos moleculares implicados en los efectos de las procianidinas de uva, aumenta el conocimiento sobre estos compuestos, así como su aplicabilidad en diferentes estados metabólicos alterados. De esta manera, se ha propuesto que la activación de FXR podría usarse como una estrategia en el tratamiento de la hiperlipidemia o la resistencia a la insulina. Así, las procianidinas emergen como un importante agente terapéutico, cuya importancia radica en la amplia presencia de estos compuestos en la dieta.
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Erqou, Sebhat. "Lipoprotein(a) and the risk of vascular disease." Thesis, University of Cambridge, 2010. https://www.repository.cam.ac.uk/handle/1810/225182.
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Background: Lipoprotein(a) [Lp(a)] is composed of a low density-lipoprotein (LDL) particle and a glycoprotein molecule known as apolipoprotein(a) [apo(a)]. Apo(a) exists in several differently-sized isoforms and is responsible for the unique properties of Lp(a). Although Lp(a) has been known for the past 40 years its relationship with coronary heart disease (CHD) has not been characterized in sufficient detail. Whether Lp(a) causes CHD is not clear. Furthermore, the role of apo(a) isoform variation and other sources of Lp(a) heterogeneity (e.g., level of oxidized phospholipids) in Lp(a)-disease association has not been determined. Objectives: To characterize in detail the association of circulating Lp(a) levels with the risk CHD To assess the nature of Lp(a)-CHD association using an integrative genetic study To explore the role of Lp(a) heterogeneity in its association with CHD Data sources: 1. The Emerging Risk Factors Collaboration (ERFC) database (36 studies, 127,000 participants) 2. The European Prospective Investigation of Cancer – Norfolk (EPIC-Norfolk) study (2200CHD cases, 2200 controls) 3. The Pakistani Risk of Myocardial Infarction Study (PROMIS) (1800 MI cases and 1800 controls) 4. Systematic quantitative reviews of published epidemiological studies Results: ERFC data - Analyses of cross-sectional data on up to 127,000 participants (predominantly of European descent) demonstrated that Lp(a) is generally not strongly correlated with known CHD risk factors. Weakly positive correlations were observed with LDL-cholesterol, apolipoprotein B100 and fibrinogen. Levels were over 2-fold higher in Blacks compared to Whites. Analyses of available data on repeat measurements in 6600 participants demonstrated that Lp(a) values have very high long-term within-person consistency (regression dilution ratio ~ 0.9). Outcome data involved 9300 incident CHD events, 1900 ischaemic strokes and 8100 nonvascular deaths. The risk ratio for CHD per 1SD higher Lp(a) concentration, adjusted for age, sex, lipids and other conventional vascular risk factors, was 1.13 (95% CI, 1.09-1.18). The corresponding risk ratios for ischaemic stroke and nonvascular death were 1.10 (1.02 – 1.18) and 1.01 (0.98-1.05), respectively. Data were too limited to assess association in nonwhites. PROMIS data – the adjusted odds ratio for MI in South Asians was comparable to that of Europeans. EPIC-Norfolk genetic data - The odds ratio for CHD per 1-SD higher Lp(a) concentration, after adjustment for cardiovascular risk factors, was 1.37 (1.20-1.56). Tagging SNPs rs10455872 and rs11751605 (minor allele frequency: 8% and 18%, respectively) were associated with 207% (95% CI, 188 - 227%) and 38% (31 - 46%) higher Lp(a) concentrations per copy of minor allele, respectively. These SNPs accounted for 35% and 5% of the variation in circulating Lp(a) levels, respectively, and were associated with an odds ratio for CHD of 1.34 (1.14-1.58) and 1.17 (1.04-1.33), respectively. The observed SNP-CHD associations were consistent with expected odds ratios corresponding to the Lp(a) effect of the SNPs. Systematic reviews – meta-analysis of published data from 40 studies (11,300 cases, 47,000 controls) demonstrated that people with smaller apo(a) isoforms have about a 2-fold higher risk of CHD or ischemic stroke than those with larger isoforms. Meta-analysis of published data from 10 studies (1500 cases, 10,200 controls) showed that people in the top third of baseline distribution of oxidized LDL levels have a 1.8-fold higher risk of CHD than those in bottom third. EPIC-Norfolk biomarker data – Levels of oxidized phospholipids were strongly correlated with Lp(a) concentration (r = 0.7, p-value < 0.0001). One SD higher concentration of oxidized phospholipids was associated with an adjusted odds ratio for CHD of 1.31 (1.15-1.49). The risk ratio was no longer significant after adjustment for Lp(a) concentration (1.08; 95% CI, 0.91-1.29). Conclusion: Lp(a) concentration is specifically, continuously and independently associated with the risk of ischaemic vascular outcomes. Available evidence supports the causal role of the particle in CHD. Lp(a) appears to induce vascular damage through causal mechanisms that involve apo(a) isoforms and oxidized phospholipids. A comprehensive study of markers of Lp(a) heterogeneity should help to understand the full impact of Lp(a) on cardiovascular diseases. In addition, further study is needed in nonwhites to assess the relevance of the factor to vascular disease risk in these populations.
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Yao, Zemin. "Phosphatidylcholine biosynthesis and lipoprotein secretion in rat hepatocytes." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/29220.
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Young male rats fed a choline-deficient diet for three days accumulated triacylglycerol (TG) in the liver, and had reduced very low density lipoprotein (VLDL), but not high density lipoprotein (HDL), levels in the plasma. Cultured hepatocytes obtained from these rats were used as a model system to investigate how choline deficiency affected hepatic lipogenesis, apolipoprotein synthesis and lipoprotein secretion. When the cells were cultured in a medium free of choline and methionine, the secretion of TG and phosphatidylcholine (PC) was impaired. Supplementation of choline, methionine or lysophosphatidylcholine (lysoPC) to the culture medium increased the secretion of these lipids to normal levels, and stimulated PC biosynthesis. Fractionation of the secreted lipoproteins by ultracentrifugation revealed that the reduced secretion of TG and PC from choline-deficient cells was mainly due to impaired secretion of VLDL. The secretion of HDL and lipid-free proteins (for example albumin), however, was not affected by choline and methionine deficiency. Supplementation of betaine and homocysteine also stimulated PC biosynthesis and enhanced hepatic VLDL secretion. However, supplementation of ethanolamine, N-monomethylethanol-amine or N, N-dimethylethanolamine did not correct the impaired VLDL secretion from the hepatocytes, although an active synthesis of phosphatidylmonomethyl-ethanolamine (PMME) and phosphatidyldimethylethanolamine was observed. Choline deficiency had no effect on the rate of incorporation of [³H]leucine into cellular apolipoprotein B, E and C or on the rate of disappearance of radioactivity from the labeled apolipoproteins. These results suggest that biosynthesis of PC is specifically required for hepatic VLDL (but not HDL) secretion, and any one of the three synthetic pathways, the CDP-choline pathway, methylation of phospha-tidylethanolamine (PE) or reacylation of lysoPC, is sufficient to provide the required PC. The total activity of cytidylyltransferase in liver was unchanged in choline deficiency. However, choline deficiency caused an abnormal distribution of cytidylyltransferase activity between rat liver cytosol and microsomes (mainly endoplasmic reticulum), a decrease in the cytosolic enzyme activity and an increase in the microsomal enzyme activity. In cultured hepatocytes from the choline-deficient rat, the abnormally distributed cytidylyltransferase activity could be rapidly reversed by the addition of choline, but not lysoPC, to the culture medium. The stimulated microsomal activity of cytidylyltransferase during choline deficiency might be a mechanism whereby the cells could more effectively utilize phosphocholine to maintain a normal CDP-choline level in the choline-deficient liver.
Rat liver PE N-methyltransferase catalyzes all three transmethylation reactions in the conversion of PE to PC. The in vitro activity of PE N-methyltransferase was increased in choline-deficient livers using endogenous PE as the methyl group acceptor. However, no significant changes were observed in the enzyme activity when exogenous PMME was used as the methyl group acceptor. Addition of methionine to the cultured hepatocytes obtained from choline-deficient rats resulted in a concomitant reduction in cellular PE levels and the specific activity of PE-dependent methyltransferase. However, the specific activity of PMME-dependent methyltransferase was not significantly altered upon the addition of methionine. No change in PE N-methyltransferase activity was observed in the cultured hepatocytes supplemented with choline. Immunoblotting of PE
N-methyltransferase, in crude liver microsomes and in membrane fractions of cultured hepatocytes, revealed that the enzyme mass was not altered by choline and methionine deficiency. Thus, hepatic PE N-methyltransferase is preserved in choline deficiency, and its activity is probably dependent on the availability of metabolic substrates (i.e. methionine and PE).Medicine, Faculty of
Biochemistry and Molecular Biology, Department of
Graduate